Brown Monica E, Miranda Verda E, Nevills Simone, Hu Ruiying, Dadi Prasanna K, Simmons Alan J, Xu Yanwen, Yang Yilin, Yagan Mahircan, Najam Sadia, Sampson Leesa L, Magnuson Mark A, Jacobson David A, Lau Ken S, Hodges Emily, Gu Guoqiang
Program in Developmental Biology, Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Center for Stem Cell Biology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Nat Commun. 2025 Jul 1;16(1):5758. doi: 10.1038/s41467-025-60831-0.
Endocrine islet β cells comprise heterogenous subtypes with different gene expression and function levels. Here we study when/how this heterogeneity is induced and how long each subtype maintains its characteristic properties. We show that islet progenitors with distinct gene expression and DNA methylation patterns produce β-cell subtypes of different secretory function, proliferation rate, and viability in male and female mice. These subtypes have differential gene expression that regulates insulin vesicle production or stimulation-secretion coupling and differential DNA methylation in the putative enhancers of these genes. Maternal obesity, a major diabetes risk factor, reduces the proportion of the β-cell subtype with higher levels of glucose responsiveness. The gene signature that defines mouse β-cell subtypes can reliably divide human cells into two sub-populations, with the one having higher predicted glucose responsiveness reduced in diabetic donors. These results suggest that β-cell subtypes can be derived from islet progenitor subsets modulated by maternal nutrition.
内分泌胰岛β细胞由具有不同基因表达和功能水平的异质亚型组成。在此，我们研究这种异质性是何时/如何被诱导的，以及每种亚型维持其特征特性的时间。我们发现，具有不同基因表达和DNA甲基化模式的胰岛祖细胞在雄性和雌性小鼠中产生具有不同分泌功能、增殖率和活力的β细胞亚型。这些亚型具有调节胰岛素囊泡产生或刺激-分泌偶联的差异基因表达，以及这些基因推定增强子中的差异DNA甲基化。母亲肥胖是一种主要的糖尿病风险因素，它会降低葡萄糖反应性较高的β细胞亚型的比例。定义小鼠β细胞亚型的基因特征能够可靠地将人类细胞分为两个亚群，其中预测葡萄糖反应性较高的亚群在糖尿病供体中减少。这些结果表明，β细胞亚型可源自受母体营养调节的胰岛祖细胞亚群。
